tbuckley/cabot-search huggingface dataset:
Abstract 326: Engineered toxin bodies (ETBs) targeting Trop2
Authors: Garrett L. Cornelison, Adam Bartos, Brigitte Brieschke, Jessica Momb, Ileana Pedraza, Elizabeth M. Kapeel, Rebecca Martin, Channing Pletka, Adrian Gonzalez, Joseph D. Dekker, Jay Zhao, John Majercak, Garrett L. Robinson
Journal: Cancer Research (2022)

Abstract Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forced internalization, undergoing retrograde translocation to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes resulting in the inhibition of protein synthesis and induction of apoptosis through ribotoxic stress mechanisms. Additionally, Molecular Templates has developed the Antigen Seeding Technology (AST) platform to generate ETBs with the unique ability to deliver foreign protein antigen to targeted populations of tumor cells. This MOA allows for the intracellular processing of antigen and subsequent surface MHC-I presentation required for activation of a re-directed T lymphocyte response and the capacity to restore a functional immune clearance program against the tumor. Three ETBs are in clinical development (MT-5111 targeting HER2, MT-0169 targeting CD38, and AST enabled MT-6402 targeting PD-L1). The novel mechanisms of action have potential benefit in different indications including in the relapsed setting, when disease has progressed after chemotherapies and other targeted therapies, and additionally may be able to combine with standard of care. ETBs are being developed that target other cell surface receptors expressed on solid tumors including tumor-associated calcium signal transducer 2 (Trop2). Trop2 is a clinically validated target of antibody drug conjugate (ADC) therapy in metastatic triple-negative breast cancer (mTNBC) and other cancers such as metastatic urothelial carcinoma (mUC). In vitro, tumor cells expressing Trop2 are effectively, specifically, and directly killed with picomolar activity by targeted ETBs. AST enabled Trop2 targeted ETBs are capable of delivering viral antigens for multiple HLA types and inducing cytokine secretion and T-cell mediated killing in a co-culture assay of Trop2 target cells with antigen matched HLA type and antigen specific T-cells. These pre-clinical in vitro data suggest AST enabled Trop2 targeted ETBs have the potential to deplete Trop2 positive malignancies through multiple unique mechanisms of action. Citation Format: Garrett L. Cornelison, Adam Bartos, Brigitte Brieschke, Jessica Momb, Ileana Pedraza, Elizabeth M. Kapeel, Rebecca Martin, Channing Pletka, Adrian Gonzalez, Joseph D. Dekker, Jay Zhao, John Majercak, Garrett L. Robinson. Engineered toxin bodies (ETBs) targeting Trop2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 326.
Re: Øyvind Ulvik, Mathias Sørstrand Æsøy, Patrick Juliebø-Jones, Peder Gjengstø, Christian Beisland. Thulium Fibre Laser Versus Holmium:YAG for Ureteroscopic Lithotripsy: Outcomes from a Prospective Randomised Clinical Trial. Eur Urol. 2022;82:73–79
Authors: Jinze Li, Yin Huang, Dehong Cao, Qiang Wei
Journal: European Urology (2022)
Abstract 3568: Robust and potent dendritic cells for cancer immunotherapy
Authors: Waqas Azeem, Seyed Mohammad Lellahi, Yaping Hua, Anne Margrete Øyan, Benjamin Gabriel, Karl-Henning Kalland
Journal: Cancer Research (2022)

Abstract Background: Dendritic cells (DCs) are fundamental to adaptive immunity by detecting, engulfing and presenting foreign or changed antigenic peptides to lymphocytes that thereafter initiate antigen-specific immune attacks. DC-based immunotherapy against cancer has been promising for a long time, but has not yet met expectations. Cancer cell heterogeneity and numerous immune evasion mechanisms represent challenges. According to textbook renderings, DCs may induce either tolerance or immune activation depending upon the nature of the encountered antigen and the status of the microenvironment. Recently, we have discovered a more complicated scenario according to which monocyte-derived DCs (moDCs) exhibit dual pro- and anti-inflammatory features, suggesting that selected conditions that enhance pro-inflammatory features and counteract tolerogenic features could generate more robust and potent DCs for cancer therapy. Materials and Methods: Healthy blood donor buffy coats were used for the isolation of monocytes and conventional CD141+ and CD1c+ natural circulating DCs. IL-4 and GM-CSF were used to differentiate monocytes into immature moDCs. Toll-like receptor agonists were used to induce DC maturation, and specific agonists and inhibitors were tested in different DC variants. Flow cytometry, ELISA determination of cytokine secretion, HPLC-based quantitation of kynurenine secretion, genome-wide gene expression analyses and functional assays, such as antigen uptake, migration and the mixed leukocyte reaction were used for evaluation of treated DCs. Results: Conventional DCs were more susceptible to apoptosis, and dependent upon culture conditions, than moDCs. Inhibition of β-catenin signaling stimulated several pro-inflammatory features, e.g. increased IL-12 and decreased IL-10 secretion, with reciprocal effects caused by β-catenin stimulation. Maturation of moDCs was accompanied by very strong induction of indoleamine 2, 3-dioxygenase 1 (IDO1) transcription and paralleled by increased kynurenine secretion, but this was partially counteracted by β-catenin stimulation. Conclusions: Preparation of more potent DCs for cancer therapy needs to take into account DC longevity and conflicting activation patterns of pro- and anti-inflammatory abilities. Citation Format: Waqas Azeem, Seyed Mohammad Lellahi, Yaping Hua, Anne Margrete Øyan, Benjamin Gabriel, Karl-Henning Kalland. Robust and potent dendritic cells for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3568.
Abstract 5194: BALB/c mice with humanized VISTA: A novel GEMM for preclinical evaluation of therapeutic antibodies against VISTA
Authors: Weiwei Yu, Honghong Bao, Shuai Li, Chao Ju, Hongyan Sun, Hao Qi, Cunxiang Ju, Jing Zhao, Xiang Gao
Journal: Cancer Research (2022)

Abstract VISTA, also known as PD1H, is an immune-checkpoint receptor mainly expressed in immune cells, including macrophages, conventional dendritic cells, monocytes and circulating neutrophils. As a negative regulator of T cell activation, VISTA inhibits T cell proliferation and attenuates the production of cytokines. Studies have shown that VISTA expression is increased in infiltrating immune cells found in the tumor microenvironment and that blocking pathways that lead to VISTA activation can enhance antitumor immune responses in mice. Based on this, antibodies targeting VISTA are promising leads for cancer therapy. Preclinical efficacy evaluation of antibodies again human VISTA requires the expression of human VISTA in animal models, since difference in extracellular domains may affect antibody recognition while the overall homology between the two proteins is only 77%. To meet this need, we established a humanized mouse model in which the extracellular domain of mVISTA is replaced with that of hVISTA while the trans-membrane and cytoplasmic domains remain intact. In order to confirm the activity of the chimeric protein in our mice, we evaluated the anti-tumor effect of proven VISTA antibodies in homozygous hVISTA mice engrafted with CT26 tumor subcutaneously. Consistent with previous studies, the growth of CT26 tumor was inhibited after VISTA antibody treatment, indicating the humanized VISTA mice are suitable for efficacy evaluation of human VISTA antibodies. Moreover, we evaluated the anti-tumor effect of a combination of PD-L1 antibody and VISTA antibody in these mice. Interestingly, the combined use of PD-L1 antibody and VISTA antibody led to significantly enhanced tumor regression than either antibody. Taken together, BALB/c-hVISTA mouse is a novel non-human animal model appropriate for preclinical efficacy study of human VISTA antibodies. Citation Format: Weiwei Yu, Honghong Bao, Shuai Li, Chao Ju, Hongyan Sun, Hao Qi, Cunxiang Ju, Jing Zhao, Xiang Gao. BALB/c mice with humanized VISTA: A novel GEMM for preclinical evaluation of therapeutic antibodies against VISTA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5194.
Granzyme K <sup>+</sup> CD8 T cells form a core population in inflamed human tissue
Authors: A. Helena Jonsson, Fan Zhang, Garrett Dunlap, Emma Gomez-Rivas, Gerald F. M. Watts, Heather J. Faust, Karishma Vijay Rupani, Joseph R. Mears, Nida Meednu, Runci Wang, Gregory Keras, Jonathan S. Coblyn, Elena M. Massarotti, Derrick J. Todd, Jennifer H. Anolik, Andrew McDavid, Kevin Wei, Deepak A. Rao, Soumya Raychaudhuri, Michael B. Brenner
Journal: Science Translational Medicine (2022)

T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK
Abstract 5820: NF-κB signaling regulates miRNA expression in ovarian cancer
Authors: Rahul D. Kamdar, Brittney S. Harrington, Soumya Korrapati, Nathan Wong, Carrie D. House, Christina M. Annunziata
Journal: Cancer Research (2022)

Abstract Epithelial ovarian cancer (EOC) remains the fifth leading cause of cancer related death in women worldwide, partly due to the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. Previous studies described the role of the NF-kB pathway in promoting TIC chemoresistance and survival through the action of key transcription factors (TFs) like RelA and RelB. These TFs serve as key master regulators of genes important for the inflammatory response, which also overlap with the regulation of targets associated with cancer promotion. We previously showed that RelA and RelB exert different effects in ovarian cancer cells, with RelB relatively more important for tumor initiation. In this study, we hypothesize that NF-kB signaling regulates the expression of several microRNAs (miRNAs) differentially through RelA and RelB to promote TIC survival and proliferation. miRNAs comprise a subset of small, noncoding RNAs that regulate gene expression and present potential therapeutic targets for clinical use. Inducible shRNA stably was expressed in OV90 EOC cells to knockdown RelA or RelB; cells were subsequently analyzed by miR-seq to identify differentially expressed miRNAs in cells grown in TIC vs adherent (adh) conditions. To validate the miR-seq findings, we performed qPCR assays of the candidate miRNAs differentially expressed in TIC or adh conditions with RelA or RelB knocked down. We confirmed the decreased expression of oncogenic miRNAs hsa-miR-105-5p and hsa-miR-452-5p, while also confirming the increased expression of tumor suppressive miRNA hsa-miR-34a-5p observed in the miR-seq using OV90 cells. Ongoing work will validate these expression changes in additional cell lines and conduct functional assays to characterize the effect of mimicking or inhibiting these miRNAs of interest. The identification of miRNAs differentially expressed in TICs under the control of RelA or RelB will provide key insights in designing treatments against them to prevent disease relapse in patients with EOC. Citation Format: Rahul D. Kamdar, Brittney S. Harrington, Soumya Korrapati, Nathan Wong, Carrie D. House, Christina M. Annunziata. NF-κB signaling regulates miRNA expression in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5820.
Abstract 3561: Pan-cancer-specific engineered oncolytic vaccinia virus
Authors: So Young Yoo
Journal: Cancer Research (2022)

Abstract Here, we developed a novel oncolytic vaccinia virus (NOV) with the dual advantages of cancer selectivity and normal vessel reconstructive activity by replacing the viral thymidine kinase (vTk) and vaccinia growth factor (VGF) genes with genes encoding TNF-related apoptosis-inducing ligand (TRAIL) and angiopoietin 1 (Ang1), respectively. The pan-cancer-specific oncolytic potency of NOV was confirmed in various human and mouse cancer cell lines (colon, lung, liver, pancreas, cholangiocarcinoma, cervical cancer, osteosarcoma, and melanoma). Vaccinia virus (VV) treatment directly induced early apoptosis in tumors within 24 h, and this effect was enhanced with further engineering; VGF and Tk deletion with Ang1 and TRAIL insertion. Meanwhile, treatment with the conventional anti-cancer drug cisplatin did not induce apoptosis. A virus-treated mouse colon/lung cancer syngeneic model showed attenuated tumor growth, which was in accordance with the results of percent survival measurement, CD8 expression analysis, and TUNEL staining with advanced genetic engineering. Taken together, our results indicate that NOV induces cancer tissue apoptosis and anti-tumor immunity and may constitute a highly advantageous therapeutic agent for next-generation solid tumor virotherapy with pan-cancer-specific oncolytic activity and high biosafety. Citation Format: So Young Yoo. Pan-cancer-specific engineered oncolytic vaccinia virus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3561.
Immunization with a self-assembling nanoparticle vaccine displaying EBV gH/gL protects humanized mice against lethal viral challenge
Authors: Harman Malhi, Leah J. Homad, Yu-Hsin Wan, Bibhav Poudel, Brooke Fiala, Andrew J. Borst, Jing Yang Wang, Carl Walkey, Jason Price, Abigail Wall, Suruchi Singh, Zoe Moodie, Lauren Carter, Simran Handa, Colin E. Correnti, Barry L. Stoddard, David Veesler, Marie Pancera, James Olson, Neil P. King, Andrew T. McGuire
Journal: Cell Reports Medicine (2022)

Epstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 165,000 deaths annually. EBV is also the etiological agent of infectious mononucleosis and is linked to multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine would have a significant global health impact. EBV is orally transmitted and has tropism for epithelial and B cells. Therefore, a vaccine would need to prevent infection of both in the oral cavity. Passive transfer of monoclonal antibodies against the gH/gL glycoprotein complex prevent experimental EBV infection in humanized mice and rhesus macaques, suggesting that gH/gL is an attractive vaccine candidate. Here, we evaluate the immunogenicity of several gH/gL nanoparticle vaccines. All display superior immunogenicity relative to monomeric gH/gL. A nanoparticle displaying 60 copies of gH/gL elicits antibodies that protect against lethal EBV challenge in humanized mice, whereas antibodies elicited by monomeric gH/gL do not. These data motivate further development of gH/gL nanoparticle vaccines for EBV.
Abstract 2769: Advance understanding of the tumor microenvironment with multiplex immunofluorescence
Authors: Bhavika Patel, Stephanie Allen, Brittney Boldt, Najiba Mammadova, Agnes Haggerty, Navi Mehra
Journal: Cancer Research (2022)

Abstract Immunotherapy and precision medicine are rapidly developing approaches to cancer therapy. Biomarkers that detect the tumor and tumor microenvironment allow for the development of strategies that accelerate the advancement of treatments to enhance a patient’s immune system. Akoya’s MOTiF™ PD-1/PD-L1 Panel is a validated, multiplex immunoassay enabling detection of the 6 most clinically relevant immuno-oncology and spatial biomarkers: PD-1, PD-L1, FoxP3, CD8, CD68, and PanCK. The MOTiF™ PD-1/PD-L1 Panel was used to analyze the tumor microenvironment and specifically assess immune phenotypes of different types of cancers: non-small cell lung cancer (NSCLC), colon adenocarcinoma, head and neck squamous cell carcinoma (HNSCC), and breast cancer. We demonstrate the utility of Akoya’s MOTiF™ PD-1/PD-L1 panel kit in studying the cellular diversity of various cancers while retaining spatial context. Stained slides were analyzed using the InForm® and PhenoptrReports image analysis platforms to identify and better understand spatial relationships between a variety of simple and complex cell phenotypes. The MOTiF™ PD-1/PD-L1 panel kit provides reproducibility across different tissue types. These data provide insight into the innate and adaptive immune environment for targeted design of new immunotherapies and have implications for improving the treatment paradigm across many tumor types. Citation Format: Bhavika Patel, Stephanie Allen, Brittney Boldt, Najiba Mammadova, Agnes Haggerty, Navi Mehra. Advance understanding of the tumor microenvironment with multiplex immunofluorescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2769.
Abstract 130: Pharmacological effects of selective xCT inhibition in ARID1A mutated cancer models
Authors: Christophe Henry, Philippe Péron, Anne-Marie Blanchet, Arielle Genevois-Borella, Marc Trellu, Dorothée Bourges, Philippe Lienard, Alexandra Basset, Erwan Jouannot, Christophe Philippo, Laurent Debussche, Jürgen Moll
Journal: Cancer Research (2022)

Abstract xCT is a cystine/glutamate antiporter that exports intracellular glutamate for extracellular cystine. In the intracellular space, cystine is converted into cysteine which is subsequently used for glutathione (GSH) synthesis (a major antioxidant species). ARID1A is part of the SWI-SNF remodeling complex that binds on the xCT promoter and as such controls its gene expression. ARID1A deficiency which is highly prevalent in many cancers results in downregulation of xCT, impaired GSH biosynthesis and subsequent ROS induction, raising potential rationale to target xCT in ARID1A deficient cancers. By using a selective nanomolar range xCT inhibitor, we first showed that cell lines deficient for ARID1A were significantly more sensitive to the inhibition of xCT. Effects on proliferation could be reversed by N-acetylcysteine supplementation in the culture medium. In vivo, the xCT inhibitor confirmed its drug-like properties showing significant target engagement in an ARID1A deficient ovarian cell line xenograft model together with good PK and tolerability profiles. Altogether these studies have provided evidence that a specific drug-like inhibitor of xCT can be developed. This proprietary compound was used to confirm that in vitro the deficiency of ARID1A in ovarian cancer predicts sensitivity to xCT inhibition. Further in vivo pharmacological studies are required to confirm a specific molecular context predicting sensitivity towards xCT inhibition. Citation Format: Christophe Henry, Philippe Péron, Anne-Marie Blanchet, Arielle Genevois-Borella, Marc Trellu, Dorothée Bourges, Philippe Lienard, Alexandra Basset, Erwan Jouannot, Christophe Philippo, Laurent Debussche, Jürgen Moll. Pharmacological effects of selective xCT inhibition in ARID1A mutated cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 130.
Abstract 5204: Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity
Authors: Richard Zhang, Haishan Lin
Journal: Cancer Research (2022)

Abstract CD47 is a well-studied target for cancer immunotherapy. Blocking of CD47 binding to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. Several monoclonal anti-CD47 antibodies are currently in various stages of clinical development. However, since CD47 is also expressed on normal cells such as red blood cells and platelets, anti-CD47 antibodies also caused on-target side effects during clinical evaluations, such as anemia and red blood cell hemagglutination. To minimize the on-target side effects of anti-CD47 antibodies, we have generated anti-CD47 prodrugs. By screening a phage peptide library, we identified peptides that can specifically block the anti-CD47 antibody binding activity. These peptides were fused to the humanized anti-CD47 antibody via a linker containing protease substrate sequences to derive the anti-CD47 antibody prodrug. We demonstrated that these anti-CD47 antibody prodrugs had significantly diminished CD47 binding activity and were unable to block CD47:SIRPα interaction. Upon cleavage of the anti-CD47 antibody prodrug with proteases, the antibody regained full activities in both binding to CD47 and blocking CD47:SIRPα interaction. Importantly, we showed that the anti-CD47 antibody prodrug had minimal hemagglutination and RBC binding activities. Since different tumors may have different types of protease activities, anti-CD47 prodrugs with different types of protease substrates have been generated to demonstrate that the anti-CD47 prodrug can be used for treating various tumor types. These data suggest that novel anti-CD47 antibody prodrugs are promising candidates for the next generation anti-CD47 therapeutics with improved safety profile. Citation Format: Richard Zhang, Haishan Lin. Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5204.